Looking beyond the cytogenetics in haematological malignancies: decoding the role of tandem repeats in DNA repair genes.

BACKGROUND: In cancer research, one of the most significant findings was to characterize the DNA repair deficiency as carcinogenic. Amongst the various repair mechanisms, mismatch repair (MMR) and direct reversal of DNA damage systems are designated as multilevel safeguards in the human genome. Defects in these elevate the rate of mutations and results in dire consequences like cancer. Of the several molecular signatures in human genome, tandem repeats (TRs) appear at various frequencies in the exonic, intronic, and regulatory regions of the DNA. Hypervariability among these repeats in the coding and non-coding regions of the genes is well characterized for solid tumours, but its significance in haematologic malignancies remains to be explored. The purpose of our study was to elucidate the role of nucleotide repeat instability in the coding and non-coding regions of 10 different repair genes in myeloid and lymphoid cell lines compared to the control samples. METHODS AND RESULTS: We selected MMR deficient extensively studied microsatellite instable colorectal cancer (HCT116), and MMR proficient breast cancer (MCF-7) cells along with underemphasized haematologic cancer cell lines to decipher the hypermutability of tandem repeats. A statistically significant TR variation was observed for MSH2 and MSH6 genes in 4 and 3 of the 6 cell lines respectively. KG1 (AML) and Daudi (Burkitt's lymphoma) were found to have compromised DNA repair competency with highly unstable nucleotide repeats. CONCLUSION: Taken together, the results suggest that mutable TRs in intronic and non-intronic regions of repair genes in blood cancer might have a tumorigenic role. Since this is a pilot study on cell lines, high throughput research in large cohorts can be undertaken to reveal novel diagnostic markers for unexplained blood cancer patients with normal karyotypes or otherwise with karyotypic defects.

Revisiting the melanomagenic pathways and current therapeutic approaches.

Melanoma is one of the most aggressive forms of skin cancer with a steady increase in global incidence and mortality rate over the past five decades. Paradoxically, both reduced and excessive sun exposure has been linked to increased risk of melanoma incidence and death. Although the histological classification of melanoma is useful in diagnosis, its molecular subtypes are often determined by somatic mutations, which could be UV-dependent or -independent. Multiple genes involved in cancer development are often mutated dysregulating molecular pathways with concomitant phenotypic heterogeneity. Hence, treating melanoma has been a challenge, with patients experiencing poor clinical outcomes to current therapeutic options. This presents an unmet need to understand the interaction of molecular networks underpinning melanogenesis. This review describes the crosstalk of signaling cascades in melanoma development and the putative druggable targets, with the view of elucidating newer and better therapeutic strategies for the disease.

The novel Isatin analog KS99 targets stemness markers in acute myeloid leukemia.

Leukemic stem cells are multipotent, self-renewing, highly proliferative cells that can withstand drug treatments. Although currently available treatments potentially destroy blast cells, they fail to eradicate leukemic progenitor cells completely. Aldehyde dehydrogenase and STAT3 are frequently up-regulated in pre-leukemic stem cells as well as in acute myeloid leukemia (AML) expressing the CD34+CD38- phenotype. The Isatin analog, KS99 has shown anticancer activity against multiple myeloma which may, in part, be mediated by inhibition of Bruton's tyrosine kinase activation. Here we demonstrate that KS99 selectively targets leukemic stem cells with high aldehyde dehydrogenase activity and inhibits phosphorylation of STAT3. KS99 targeted cells co-expressing CD34, CD38, CD123, TIM-3, or CD96 immunophenotypes in AML, alone or in combination with the standard therapeutic agent cytarabine. AML with myelodysplastic-related changes was more sensitive than de novo AML with or without NPM1 mutation. KS99 treatment reduced the clonogenicity of primary human AML cells as compared to normal cord blood mononuclear cells. Downregulation of phosphorylated Bruton's tyrosine kinase, STAT3, and aldehyde dehydrogenase was observed, suggesting interaction with KS99 as predicted through docking. KS99 with or without cytarabine showed in vivo preclinical efficacy in human and mouse AML animal models and prolonged survival. KS99 was well tolerated with overall negligible adverse effects. In conclusion, KS99 inhibits aldehyde dehydrogenase and STAT3 activities and causes cell death of leukemic stem cells, but not normal hematopoietic stem and progenitor cells.

A study of deregulated MMR pathways and anticancer potential of curcuma derivatives using computational approach.

Plant derived products have steadily gained momentum in treatment of cancer over the past decades. Curcuma and its derivatives, in particular, have diverse medicinal properties including anticancer potential with proven safety as supported by numerous in vivo and in vitro studies. A defective Mis-Match Repair (MMR) is implicated in solid tumors but its role in haematologic malignancies is not keenly studied and the current literature suggests that it is limited. Nonetheless, there are multiple pathways interjecting the mismatch repair proteins in haematologic cancers that may have a direct or indirect implication in progression of the disease. Here, through computational analysis, we target proteins that are involved in rewiring of multiple signaling cascades via altered expression in cancer using various curcuma derivatives (Curcuma longa L. and Curcuma caesia Roxb.) which in turn, profoundly controls MMR protein function. These biomolecules were screened to identify their efficacy on selected targets (in blood-related cancers); aberrations of which adversely impacted mismatch repair machinery. The study revealed that of the 536 compounds screened, six of them may have the potential to regulate the expression of identified targets and thus revive the MMR function preventing genomic instability. These results reveal that there may be potential plant derived biomolecules that may have anticancer properties against the tumors driven by deregulated MMR-pathways.

Toxic impacts and industrial potential of graphene.

Advancement in the field of nanotechnology has increased the synthesis and exploitation of graphene-like nanomaterials. Graphene is a two-dimensional planar and hexagonal array of carbon atoms. Due to its flexible nature graphene and its derivatives have several significant prospects extending from electronics to life sciences and drug delivery systems. In this review, we enlist some of the toxic effects of graphene family nanomaterials (GFNs) in various aspects of biosystems viz., in vitro, in vivo, microbial, molecular and environmental. We also appreciate their extensive and promising applications though with some underlying challenges. This review also draws attention toward current and future prospect of global graphene market for wide-range commercialization.

Microsatellite Instability and Promoter Hypermethylation of DNA repair genes in Hematologic Malignancies: a forthcoming direction toward diagnostics.

OBJECTIVE: The objective of our review is to highlight the significance of microsatellite hypervariation in diagnostics of hematologic malignancies. METHODS: For the past few decades, extensive experiments in cancer research have explored all the possible pathways and a number of deleterious mutations that either make the tumor suppressor genes (TSGs) dysfunctional or cause the proto-oncogenes to behave abnormally by changing the cellular phenotype hence rendering disease. To prevent the deleterious effects of mutations and to protect the genomic integrity, our system possesses multiple repair mechanisms. DNA Mismatch Repair (MMR) and Direct Reversal of Damage (DRD) are two repair mechanisms which help in removal of faulty base pairs and alkyl adduct formation respectively to avoid long term effects of toxicity, tumorigenesis and mutagenesis. There are nine major MMR genes - MutS homolog (MSH2, MSH3, MSH4, MSH5, MSH6), MutL homolog (MLH1, MLH3), human post-meiotic segregation genes (PMS1, PMS2), and three major damage reversal genes - O6-methylguanine-DNA-methyltransferase (MGMT), ABH2 and DEPC1. RESULTS: Any malfunction in DNA repair machinery can cause microsatellite instability (MSI), a form of genomic abnormality with hyper mutable repeats that is directly associated with cancer. Microsatellites are short, repetitive sequences, non-randomly distributed and localized in 3'-UTR (Untranslated Region), introns, coding regions and promoters. Besides MSI, evidence on promoter hypermethylation of selected repair genes also points toward a prominent reason for cancer initiation and progression. CONCLUSION: The presence of specific microsatellite marker hyper-mutability and consistent promoter hypermethylation in leukemia or lymphoma can be considered as a part of routine diagnostic test in clinical laboratories.

Gut microbiota: an Indicator to Gastrointestinal Tract Diseases.

PURPOSE: Gut microbiota is predicted to play a key role in manifestation of gastrointestinal tract cancers. The human gastrointestinal tract is a complex and abundant network of microbial community. Gut microbiota depicts the microbe population living in our intestine. Humans harbour more than 10(14) microbes in the gut, and the diversity and densities of the microbiota increase from stomach to colon. METHODS: The beneficial relationship between endogenous microbiota and the eukaryotic hosts helps in maintaining various metabolic activities of the body as well as temperature and pH balance. Studies using culturing methods have suggested that the oesophagus is either sterile or contains only a few transient microbes that originates from the oropharynx by swallowing or from the stomach by gastroesophageal reflux. However, metagenomics suggest that large numbers of uncultured organisms are harboured in the human gut. RESULTS: Observations suggest that research directed towards manipulation of the gut microbiota can be employed in prevention as well as treatment of these conditions. Well-designed, randomized, placebo-controlled human studies using probiotics and/or prebiotics are necessary to formulate the directions for prevention and therapy. CONCLUSIONS: Change in gut microbes in gastrointestinal (GI) tract may have major implication in gastric cancer, the fifth most occurring malignancy in the world. Affected population manifests multiple conditions and diseases, which majorly includes inflammatory bowel disease and colorectal malignancy.